A prospective evaluation of the diagnostic accuracy of the point-of-care VISITECT CD4 Advanced Disease test in seven countries.

BACKGROUND: CD4 measurement is pivotal in the management of advanced HIV disease. VISITECT® CD4 Advanced Disease (AccuBio Limited, Alva, UK; VISITECT) is an instrument-free, point-of-care, semi-quantitative test allowing visual identification of a CD4 ≤200 cells/µl, or >200 cells/µl from finger-prick or venous blood. METHODS: As part of a diagnostic accuracy study of FUJIFILM SILVAMP TB LAM (clinicaltrials.gov: NCT04089423), people living with HIV of ≥18 years old were prospectively recruited in seven countries from outpatient departments if a tuberculosis symptom was present, and from inpatient departments. Participants provided venous blood for CD4 measurement using flow cytometry (reference standard) and finger-prick blood for VISITECT (index text), performed at point-of-care. Sensitivity, specificity, and positive and negative predictive values of VISITECT to determine a CD4 ≤200 cells/µl were evaluated. RESULTS: Among 1604 participants, the median flow cytometry CD4 was 367 (IQR 128-626) cells/µl and 521 (32.5%) had a CD4 ≤200 cells/µl. VISITECT sensitivity was 92.7% (483/521, 95% CI 90.1-94.7%) and specificity was 61.4% (665/1083, 95% CI 58.4-64.3%). For participants with a CD4 between 0-100, 101-200, 201-300, 301-500, and >500 cells/µl, VISITECT misclassified 4.5% (95% CI 2.5-7.2%), 12.5 (95% CI 8.0-18.2%), 74.1% (95% CI 67.0-80.5%), 48.0% (95% CI 42.5-53.6%), and 22.6% (95% CI 19.3-26.3%), respectively. CONCLUSIONS: VISITECT's sensitivity, but not specificity, met the World Health Organization's minimal sensitivity and specificity threshold of 80% for point-of-care CD4 tests. VISITECT's quality needs to be assessed and its accuracy optimized. VISITECT´s utility as CD4 triage test should be investigated.

Prospective multicentre accuracy evaluation of the FUJIFILM SILVAMP TB LAM test for the diagnosis of tuberculosis in people living with HIV demonstrates lot-to-lot variability.

There is an urgent need for rapid, non-sputum point-of-care diagnostics to detect tuberculosis. This prospective trial in seven high tuberculosis burden countries evaluated the diagnostic accuracy of the point-of-care urine-based lipoarabinomannan assay FUJIFILM SILVAMP TB LAM (FujiLAM) among inpatients and outpatients living with HIV. Diagnostic performance of FujiLAM was assessed against a mycobacterial reference standard (sputum culture, blood culture, and Xpert Ultra from urine and sputum at enrollment, and additional sputum culture ≤7 days from enrollment), an extended mycobacterial reference standard (eMRS), and a composite reference standard including clinical evaluation. Of 1637 participants considered for the analysis, 296 (18%) were tuberculosis positive by eMRS. Median age was 40 years, median CD4 cell count was 369 cells/ul, and 52% were female. Overall FujiLAM sensitivity was 54·4% (95% CI: 48·7-60·0), overall specificity was 85·2% (83·2-87·0) against eMRS. Sensitivity and specificity estimates varied between sites, ranging from 26·5% (95% CI: 17·4%-38·0%) to 73·2% (60·4%-83·0%), and 75·0 (65·0%-82·9%) to 96·5 (92·1%-98·5%), respectively. Post-hoc exploratory analysis identified significant variability in the performance of the six FujiLAM lots used in this study. Lot variability limited interpretation of FujiLAM test performance. Although results with the current version of FujiLAM are too variable for clinical decision-making, the lipoarabinomannan biomarker still holds promise for tuberculosis diagnostics. The trial is registered at clinicaltrials.gov (NCT04089423).

COVID-19 self-testing using antigen rapid diagnostic tests: Feasibility evaluation among health-care workers and general population in Malawi.

BACKGROUND: COVID-19 testing is critical for identifying cases to prevent transmission. COVID-19 self-testing has the potential to increase diagnostic testing capacity and to expand access to hard-to-reach areas in low-and-middle-income countries. We investigated the feasibility and acceptability of COVID-19 self-sampling and self-testing using SARS-CoV-2 Antigen-Rapid Diagnostic Tests (Ag-RDTs). METHODS: From July 2021 to February 2022, we conducted a mixed-methods cross-sectional study examining self-sampling and self-testing using Standard Q and Panbio COVID-19 Ag Rapid Test Device in Urban and rural Blantyre, Malawi. Health care workers and adults (18y+) in the general population were non-randomly sampled. RESULTS: Overall, 1,330 participants were enrolled of whom 674 (56.0%) were female and 656 (54.0%) were male with 664 for self-sampling and 666 for self-testing. Mean age was 30.7y (standard deviation [SD] 9.6). Self-sampling usability threshold for Standard Q was 273/333 (82.0%: 95% CI 77.4% to 86.0%) and 261/331 (78.8%: 95% CI 74.1% to 83.1%) for Panbio. Self-testing threshold was 276/335 (82.4%: 95% CI 77.9% to 86.3%) and 300/332 (90.4%: 95% CI 86.7% to 93.3%) for Standard Q and Panbio, respectively. Agreement between self-sample results and professional test results was 325/325 (100%) and 322/322 (100%) for Standard Q and Panbio, respectively. For self-testing, agreement was 332/333 (99.7%: 95% CI 98.3 to 100%) for Standard Q and 330/330 (100%: 95% CI 99.8 to 100%) for Panbio. Odds of achieving self-sampling threshold increased if the participant was recruited from an urban site (odds ratio [OR] 2.15 95% CI 1.44 to 3.23, P < .01. Compared to participants with primary school education those with secondary and tertiary achieved higher self-testing threshold OR 1.88 (95% CI 1.17 to 3.01), P = .01 and 4.05 (95% CI 1.20 to13.63), P = .02, respectively. CONCLUSIONS: One of the first studies to demonstrate high feasibility and acceptability of self-testing using SARS-CoV-2 Ag-RDTs among general and health-care worker populations in low- and middle-income countries potentially supporting large scale-up. Further research is warranted to provide optimal delivery strategies of self-testing.

Utility of Xpert MTB/RIF Ultra and digital chest radiography for the diagnosis and treatment of TB in people living with HIV: a randomised controlled trial (XACT-TB).

BACKGROUND: TB is a leading cause of morbidity among HIV positive individuals. Accurate algorithms are needed to achieve early TB diagnosis and treatment. We investigated the use of Xpert MTB/RIF Ultra in combination with chest radiography for TB diagnosis in ambulatory HIV positive individuals. METHODS: This was a randomised controlled trial with a 2-by-2 factorial design. Outpatient HIV clinic attendees with cough were randomised to four arms: Arm 1-Standard Xpert/no chest radiography (CXR); Arm 2-Standard Xpert/CXR; Arm 3-Xpert Ultra/no CXR; and Arm 4-Xpert Ultra/CXR. Participants were followed up at days 28 and 56 to assess for TB treatment initiation. RESULTS: We randomised 640 participants. Bacteriologically confirmed TB treatment initiation at day 28 were: Arm 1 (8.4% [14/162]), Arm 2 (6.9% [11/159]), Arm 3 (8.2% [13/159]) and Arm 4 (5.6% [9/160]) and between Xpert Ultra group (Arms 3 and 4) (6.9% [22/319]) vs Standard Xpert group (Arms 1 and 2) (7.8% [25/321]), risk ratio 0.89 (95% CI 0.51 to 1.54). By day 56, there were also similar all-TB treatment initiations in the x-ray group (Arms 2 and 4) (16.0% [51/319]) compared with the no x-ray group (Arms 1 and 3) (13.1% [42/321]), risk ratio 1.22 (95% CI 0.84 to 1.78); however, the contribution of clinically diagnosed treatment initiations were higher in x-ray groups (50.9% vs 19.0%). CONCLUSIONS: Xpert Ultra performed similarly to Xpert MTB/RIF. X-rays are useful for TB screening but further research should investigate how to mitigate false-positive treatment initiations.

Pattern of abnormalities amongst chest X-rays of adults undergoing computer-assisted digital chest X-ray screening for tuberculosis in Peri-Urban Blantyre, Malawi: A cross-sectional study.

BACKGROUND: The prevalence of diseases other than tuberculosis (TB) detected during chest X-ray screening is poorly described in sub-Saharan Africa. Computer-assisted digital chest X-ray technology is available for TB screening and has the potential to be a screening tool for non-communicable diseases as well. Low- and middle-income countries are in a transition period where the burden of non-communicable diseases is increasing, but health systems are mainly focused on addressing infectious diseases. METHODS: Participants were adults undergoing computer-assisted chest X-ray screening for tuberculosis in a community-wide tuberculosis prevalence survey in Blantyre, Malawi. Adults with abnormal radiographs by field radiographer interpretation were evaluated by a physician in a community-based clinic. X-ray classifications were compared to classifications of a random sample of normal chest X-rays by radiographer interpretation. Radiographic features were classified using WHO Integrated Management for Adult Illnesses (IMAI) guidelines. All radiographs taken at the screening tent were analysed by the Qure.ai qXR v2.0 software. RESULTS: 5% (648/13,490) of adults who underwent chest radiography were identified to have an abnormal chest X-ray by the radiographer. 387 (59.7%) of the participants attended the X-ray clinic, and another 387 randomly sampled normal X-rays were available for comparison. Participants who were referred to the community clinic had a significantly higher HIV prevalence than those who had been identified to have a normal CXR by the field radiographer (90 [23.3%] vs. 43 [11.1%] p-value < 0.001). The commonest radiographic finding was cardiomegaly (20.7%, 95% CI 18.0-23.7). One in five (81/387) chest X-rays were misclassified by the radiographer. The overall mean Qure.ai qXR v2.0 score for all reviewed X-rays was 0.23 (SD 0.20). There was a high concordance of cardiomegaly classification between the physician and the computer-assisted software (109/118, 92.4%). CONCLUSION: There is a high burden of cardiomegaly on a chest X-ray at a community level, much of which is in patients with diabetes, heart disease and high blood pressure. Cardiomegaly on chest X-ray may be a potential tool for screening for cardiovascular NCDs at the primary care level as well as in the community.